Student Profiles: Students | Alumni | All Arta Monjazeb, MD, PhD Brielle Paolini Chris Starr, PhD Chris Lack, MD, PhD Christopher T. Whitlow, MD, PhD Dino Massoglia, MD, PhD Eric Hudgins, PhD Greg Riedlinger, MD, PhD Isabel Newton, MD, PhD Jason Hipp, MD, PhD Jason Bonomo Jenn Martelle, MD, PhD Jennifer Hipp, PhD Kim Blish, PhD Kristin Dew Weimer Kyle Binder Lan Gardner Coffman, MD, PhD Matt Schindler, MD, PhD Mitchell Ladd Nanmeng Yu Oleg Lobanov Rebecca Myer, MD, PhD Sandy An Walter Wiggins

Lan Gardner Coffman, MD, PhD

My work focuses on a novel interaction between high molecular weight kininogen (HK) and ferritin. HK is a co-factor in the intrinsic coagulation cascade and is the precursor to bradykinin (BK) and two-chain high molecular weight kininogen (HKa). BK is a potent pro-inflammatory, pro-angiogenic peptide, while HKa is pro-inflammatory and anti-angiogenic. Ferritin is a regulator of iron homeostasis acting to contain, concentrate and detoxify iron. Both ferritin and HK proteins influence similar disease processes including atherosclerosis, asthma and cancer.
HK is cleaved by the inflammatory proteases neutrophil elastase and mast cell tryptase. This may be an important mechanism to ensure the generation of BK and HKa at sites of inflammation. We show that ferritin, by reducing HK cleavage, may alter the progression of inflammation via decreased production of BK and HKa.
Ferritin binds the HK light chain, which is retained in HKa. Therefore, the ability of ferritin to alter the anti-angiogenic properties of HKa was investigated. My work demonstrates that ferritin opposes HKa’s effects on key steps in angiogenesis, leading to increased endothelial cell survival, migration and tube formation. A murine tumor model confirmed the antagonistic role of ferritin on HKa and established ferritin and HKa as regulators of tumor angiogenesis. Furthermore, a direct, high affinity association between ferritin and HKa was determined. The ferritin binding region was narrowed to a 28 amino acid sequence with anti-angiogenic properties, located within domain 5 of HKa. Overall, these findings define a novel role for ferritin in the regulation of HK biology and explore the subsequent implications of the ferritin/HK interaction in inflammation, angiogenesis and cancer.

Coffman, LG, Parsonage, D, D’Agostino R Jr, Torti, FM, Torti, SV. 2009. Regulatory effects of ferritin on angiogenesis. Proc Natl Acad Sci, Jan 13; 106(2):570-5. Epub2009 Jan 6.

Coffman, LG, Brown, JC, Johnson, DA, Parthasarathy, N, D’Agostino, Jr RB, Lively, MO, Hua, X, Tilley, SL, Muller-Esterl, WP, Willingham, MC, Torti, FM, Torti, SV. 2008. Cleavage of high molecular weight kininogen by elastase and tryptase is inhibited by ferritin. Am J Physiol Lung Cell Mol Physiol, 2008 Mar;294(3): L505-15. Epub 2008 Jan 11.

Knovich, MA, Storey, JA, Coffman, LG, Torti, SV, Torti, FM. 2009. Ferritin for the clinican. Blood Rev. May;23(3):95-104. Epub 2008 Oct. 2.

A. M. Collins , and L. M. Gardner. Partial Cytochrome b Sequences for Six Hymenoptera of the Eastern United States (2001) J Hered 92: 519-521.

American Heart Association Predoctorial Fellowship Grant, 2006-2008

Cancer Biology Retreat Presentation Award, 2006

Carroll Medal in Biology, Loyola College, 2003

Barry M. Goldwater Scholarship, 2002

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